Macular edema refers to the occurrence of edema in the macula, a region in the center of the retina involved in acute and detailed vision. Edema refers to the presence of excess interstitial fluid (or fluid in spaces between cells) in tissues. Thus the presence of excess fluid or increases in interstitial fluid pressure that increase fluid volume can result in edema.
The more severe and visually threatening forms of macular edema have been termed “clinically significant macular edema”, as explained below. Clinically significant macular edema (CSME) occurs most frequently in type II DM requiring insulin (11%), less in type II without insulin (4%) and in type I (6%). Clinically significant macular edema may appear at any stage of DR (Klein, R. et al. Ophthalmology 1989, 96: 1501–1510.). The Early Treatment Diabetic Retinopathy Study (ETDRS) defined CSME as 1.) Retinal thickening involving, or within 500μm from, the center of the macula; 2.) Hard exudate(s) (with thickening of the adjacent retina) at or within 500 μm from the center of the macula; and 3.) A zone of retinal thickening one disc area or larger in size, any part of which is within one disc diameter from the center of the macula (Arch Ophthalmol 1985, 103: 1796–1806.).
Diabetic retinopathy (DR) is a long-term consequence of diabetes mellitus (DM) that can lead to significant vision loss. It is characterized by microaneurysms, excessive vascular permeability, and areas of retinal non-perfusion and retinal neovascularization. Diabetic macular edema (DME) is the principal mechanism of vision loss in non-proliferative diabetic retinopathy and occurs primarily as the result of macular exudation. This may occur either as the result of focal leakage of exudate from one or more clusters of microaneurysms and dilated capillaries, each often surrounded by a ring of yellow, deep retinal exudates, or as a result of diffuse leakage from most of the retinal vasculature in the macular area. In general, the loss of central vision parallels the degree of intraretinal exudate. Over one-half of diabetics with macular edema will lose two or more lines of visual acuity within two years (Ferris, F. L. and Patz, A. Surv Ophthalmol 1984, May; 28 Suppl: 452–461). These patients are very common in most retina practices and the disease represents a significant public health problem.
Following diabetic retinopathy, retinal venous occlusive disease is the most common retinal vascular disorder. Central retinal vein occlusion (CRVO) is a common retinal vascular disorder with potentially blinding complications. It can be ischemic or nonischemic. Men are more commonly affected than women, age at presentation is usually in the low to mid 60s. Associated risk factors are history of systemic hypertension, cardiovascular disease, diabetes mellitus, blood hyperviscosity, glaucoma, hyperopia and others. The condition is characterized by intraretinal hemorrhages in all four quadrants, dilated and torturous retinal venules, optic disc edema and retinal edema (including macular edema).
Macular edema is common in most central retinal vein occlusions and accounts for loss of visual acuity in many eyes. A recent, large, multicenter clinical trial was conducted to assess the efficacy of grid photocoagulation for macular edema in CRVO. The treatment did reduce angiographic evidence of macular edema but visual acuity results were not significantly different in the treated and untreated group. Therefore, the Central Vein Occlusion Study does not recommend laser photocoagulation for treatment of macular edema.
Another cause of macular edema is branch retinal vein occlusion (BRVO). BRVO is caused by an obstruction of one or more than one of the branch retinal veins in the retina. There is no sex predilection and the condition is most frequent at the 7th decade of life. Associated risk factors are history of systemic hypertension, cardiovascular disease, glaucoma, increased body mass index at the age of 20 years, higher levels of alpha-2-globulin, and eyes with shorter axial lengths. The acute phase is characterized by segmental (based on the location of the occluded vein) intraretinal hemorrhage.
Beyond DME, CRVO and BRVO, the occurrence of postoperative cystoids, ocular tumors, intraocular inflammation, wet AMD, light toxicity, and retinitis pigmentosa may lead to macular edema. The occurrence of these conditions do not, however, indicate a necessary presence of macular edema. Macular edema may also be drug induced.
Currently the therapy shown to be even partially effective at reducing the rate of vision loss in patients that have macular edema is photocoagulation. However, laser photocoagulation results, in significant visual improvement in only a limited number of cases. Conclusions from the ETDRS (Ophthalmology 1991, 98:766–785) indicate that eyes with mild to moderate nonproliferative diabetic retinopathy and clinically significant macular edema, when treated with focal argon blue-green or argon green laser to microaneurysms and a grid treatment to zones of diffuse leakage and non-perfusion, show the maximum benefit of treatment. However, there appears to be little to gain from early photocoagulation in eyes where edema does not involve the center of the macula and only moderate gain, when it does (Guyer, D. R. et al. Retina—Vitreous—Macula: Diabetic Retinopathy; W. B. Saunders company. 1999, 316–344). In eyes with mild to moderate macular edema, panretinal photocoagulation is not recommended.
Although laser treatment is somewhat effective at reducing the rate of vision loss it is also a destructive treatment with unwanted side effects that can cause loss of central visual acuity and scotoma formation (Ferris, F. L. Arch Ophthalmol 1999, 117(5): 675–676). Patients with visual acuity of 20/20 or better are less likely to recognize the benefits from this aggressive treatment and more likely to notice its side effects, that can include some loss of peripheral vision, and a reduction in color and night vision. Patients often have difficulty in accepting treatment with laser photocoagulation, knowing that they potentially are going to lose some of their vision and day to day tasks such as reading and driving will be much harder to perform. In general photocoagulation is considered a less than satisfactory therapeutic regimen for the treatment of macular edema.
Photodynamic therapy is a two-step process consisting of an intravenous injection of a photosensitizer (light-activated drug) followed by the application of light of an appropriate wavelength that is absorbed by the photosensitizer. The light sources most commonly used are non-thermal lasers or light emitting diodes (LEDs). Photosensitizers accumulate in target tissues preferentially, including vascular endothelial cells and tumor cells. In combination with localized light administration, this allows for selective; treatment of the pathologic tissue. After exposure to light at a wavelength absorbed by the photosensitizer, an energy transfer cascade is initiated, culminating in the formation of singlet oxygen which generates intracellular free radicals. These free radicals can disrupt cellular structures such as the cell membrane, mitochondria, and lysosomal membranes. Photodynamic therapy has been suggested for the treatment of a wide variety of medical conditions, including cancer, autoimmunity, inflammation, cardiovascular disease, infection with pathogens, and conditions resulting from unwanted neovasculature.
Citation of documents herein is not intended as an admission that any is pertinent prior art. All statements as to the date or representation as to the contents of documents is based on the information available to the applicant and does not constitute any admission as to the correctness of the dates or contents of the documents.